Professional Documents
Culture Documents
HORMONES
Introduction to Endocrinology [07.06: Dr. J. Arbelle]
Hormone Synthesis Secretion and Characteristics [07.06: Prof. Y. Levy]
Hormone Mechanism of Action [07.06: Prof. Y. Sharoni]
Nuclear Receptors [08.06: Prof. Y. Levy]
HYPOTHALAMUS AND PITUITARY
Histology [08.06: Dr. C. Brodsky]
GH-IGF1 [09.06: Dr. E. Hershkowitz]
Acromegaly [13.06: Prof. S. Glick]
Prolactin [13.06: Prof. S. Glick]
ADH [10.06: Prof. S. Glick]
Pubertal Development GnRH [17.06: Dr. E. Hershkowitz]
THYROID AND PARATHYROID
Histology [08.06: Dr. C. Brodsky]
Thyroid Physiology [14.06: Dr. J. Arbelle]
Thyroid Pathology [15.06: Dr. G. Amitai]
Thyroid Dysfunction: Thyrotoxicosis & Hypothyroidism [15.06: Dr. J. Arbelle]
Calcium Regulating Hormones [14.06: Prof. S. Shanny]
Hypo/Hyper Calcemia [16.06: Prof. S. Shanny]
Endemic Goiter and Thyroid Nodular Disease [17.06: Dr. J. Arbelle]
ADRENAL GLAND
Histology [08.06: Dr. C. Brodsky]
Adrenal Physiology [13.06: Prof. E. Lieberman]
Adrenal Pathophysiology [10.06: Prof. I. Liberman]
Adrenal Pathology [15.06: Dr. G. Amitai]
PANCREAS AND ADIPOSE TISSUE
Histology [08.06: Dr. C. Brodsky]
Obesity [17.06: Dr. M. Maislos]
Diabetes type 1+2 Definition and Pathophysiology [20.06: Dr. I. Harman]
Oral Hypoglycemics Drugs [21.06: Dr. M. Maislos]
Complications Diabetes and DKA [21.06: Dr. I. Harman]
Hypoglycemia [22.06: Dr. M. Maislos]
Obesity- Epidemiology and Alternative Diet Approaches [24.06: Dr. I. Shai]
HORMONES
Introduction to Endocrinology [07.06: Dr. J. Arbelle]
Hormone Synthesis Secretion and Characteristics [07.06: Prof. Y. Levy]
Hormone Mechanism of Action [07.06: Prof. Y. Sharoni]
Nuclear Receptors [08.06: Prof. Y. Levy]
1: Introduction
a. hormones are molecules that produce signals either locally or at a distance
i. autocrine signaling affects the cell from which it was secreted
ii. paracrine signaling acts upon neighboring cells
iii. endocrine signaling is sent through the blood to distant receptors
iv. exocrine signaling is released into ducts on epithelial surfaces
v. signals can full into multiple categories
b. there are three major hormone classes: peptides, steroids, and amines
i. peptides/proteins: typically synthesized from preprohormone, processed in
rough ER, where signal peptide cleavage results in prohormone
(1) before translation finishes, peptide and ribosome is guided to ER by a
signal recognition particle (SRP)
(2) processed in golgi into final active hormone, and then stored in vesicles
(3) released via exocytosis, enters bloodstream (soluble), and acts on cellsurface receptors of target tissues
(4) works fast through the second messenger system
ii. steroids: synthesized from cholesterol as-needed; lipid soluble, diffuses out
of secretory cell, and transported in blood bound to carrier plasma proteins
(1) diffuses into target cell, and binds intracytoplasmic protein receptors
(2) steroid hormone-receptor complex enters nucleus and activates gene
transcription, resulting in protein synthesis slow acting
iii. amines: synthesized from tyrosine precursors, includes: thyroid hormone,
epinephrine and norepinephrine
(1) epinephrine and norepinephrine are made, stored, released, and act on
target cells like protein/peptide hormones
(2) thyroid hormone combines aspects of peptide and steroid hormones
c. hormones can be secreted in response to stimuli, maintained at relatively stable
concentrations, or secreted in a pulsatile fashion
i.
inositol
triphosphate
JAK/STAT
hCG
TSH
LH and FSH
ACTH
CRH
calcitonin
PTH
glucagon
GHRH
oxytocin
GnRH
TRH
GH
erythropoietin
leptin
cytokines
intracellular
receptors
glucocorticoids
estrogen
testosterone
progesterone
vitamin D
triiodothyronine
HYPOTHALAMUS/PITUITARY AXIS
HYPOTHALAMUS AND PITUITARY INTRODUCTION
Histology [08.06: Dr. C. Brodsky]
2: Anterior Pituitary
a. anterior pituitary: composed of five major cell types, each producing one or
more large polypeptide hormones; also called the adenohypophysis
b. the five cells are differentiated by PAS staining into three categories
i. acidophil: lactotropes (prolactin) and somatotropes (GH, 50% of cells)
ii. basophil: gonadotropes (FSH, LH), corticotropes (ACTH), thyrotropes
(TSH) mnemonic for the hormones: bases are FLAT
iii. chromophobes: unknown function
c. all five are regulated by the hypothalamic releasing and inhibiting hormones
i. these regulatory hormones converge on the median eminence (the stalk),
and are released in the primary capillary plexus
ii. blood goes from the primary plexus to the secondary capillary plexus
through they hypohyseal portal veins
(1) the system enables high con-centrations of releasing factors inside the
ant. pituitary, but nearly undetectable everywhere else
d. produces three single-chain, polypeptide hormones:
i. prolactin: large protein structurally similar to GH and human placental
lactogen, is synthesized in RER of lactotropes
(1) secreted throughout the day, but more at night; stimulated by suckling
and by some TRH cross-reaction, inhibited by dopamine
(2) promotes additional breast development during pregnancy
(3) inhibits ovulation through its effects on GnRH
(4) modus operandi is production, which is inhibited by dopamine from the
brain severing the pituitary stalk results in excess prolactin
(a) elevated in epileptic seizures
ii. growth hormone: large peptide that mainly promotes linear growth
(1) also referred to as somatotropic hormone (somatotropin)
(2) secreted in pulsatile pattern, and is usually at low concentrations
(a) higher in children and adolescents than adults
(3) released in response to GHRH, but also responds to exercise, trauma
and acute hypoglycemia; inhibited by IGF-1 and somatostatin
(a) GHRH upregulates GH transcription by increasing cAMP levels
(i) also released by grehlin (peptide hormone from the stomach)
(b) it is a counterregulatory hormone that is released in response to
hypoglycemia (like glucagon, cortisol and epinephrine)
(4) GH receptor uses JAK/STAT to make insulin-like GF in the liver (IGF-1):
actual action mostly mediated by IGF-1
(a) insulin-like growth factor (IGF-1) is made in the liver in response to
GH; works via a tyrosine-kinase receptor (like insulin)
(i) IGF-1 circulates in the blood bound to IGF-binding protein-3 and
acid labile subunit (ALS) prolongs half-life to 16 hours
(5) less tissue-specific compared to other pituitary hormones; exerts effects
throughout most of the body increased protein synthesis, fat
utilization, decreased glucose uptake into tissues
iii. adrenocorticotropic hormone: short peptide that induces synthesis of
adrenal cortical hormones (corticosteroids) by the adrenal cortex
(1) synthesized by corticotropes in the anterior pituitary due to CRH
3: Posterior Pituitary
a. posterior pituitary: hormones released from here are actually synthesized by
hypothalamic neurons transported to axon terminals in the pituitary gland
i. region containing the axon terminals is called the pars nervosa
(1) neurosecretory granulas are called herring bodies
(2) cell bodies seen here are pituicites (neuronal support cells)
ii. short peptide hormones are released in response to neuronal input
iii. the cells responsible for hormone synthesis are magnocellular neurons, that
contain paraventricular and supraoptic nuclei
iv. oxytocin and ADH are the main hormones, and they are synthesized by
cleaving prohormones in vesicles
b. oxytocin: promotes uterine contractions during labor, facilitates milk delivery by
stimulating contraction of myoepithelial cells in the breast
c. antidiuretic hormone: also called vasopressin, works to decrease plasma
osmolality by increasing reabsorption of water in kidneys
i. regulated by neurons adjacent to the hypothalamus that change shape when
extracellular osmolality changes
(1) also responds to atrial, aortic and carotid sinus baroreceptors
(2) part of parent compound neurophysin, which is also released
ii. increased by: high plasma osmolality, low plasma volume, low BP
(1) high levels strangely implicated in monogamy in mice
iii. decreased by: low plasma osmolality, high plasma volume, high BP
iv. uses a V2 adenylate cyclase receptor for its effects on the kidneys; usesa
V1 phosphoinositol receptor for its pressor effects
(1) activation of adenylate cyclase cAMP in kidneys increases synthesis
of aquaporins, and their migration to the luminal membrane (tubules)
PUBERTY
Pubertal Development GnRH [17.06: Dr. E. Hershkowitz]
1: Puberty
a. defined as gonadal maturation, secondary sex characteristics, growth spurt
i. average onset of 11 years for girls, 12 for boys
b. adrenarche: associated with puberty, its an increased secretion of androgens
and DHEAs from the adrenal cortex; increase in 17-ketosteroid production
c. thelarche: development of breasts in girls, usually first sign of puberty
d. pubarche: development of pubic hair; occurs 6 months after thelarche
e. menarche: menstrual cycles, begin about 2 years after thelarche (stage 4)
i. ovarian cycles may take 1-2 years to normalize
ii. uterus also changes shape/size over the course of female development
f. ovarian regulation: GnRH released FSH and LH produced ovaries produce
inhibin and estrogen negative feedback on first two steps
STAGE
BREAST DEVELOPMENT
PUBIC HAIR
none
curly pigmented
hairs
small adult
configuration
GENITAL MATURITY
PUBIC HAIR
none
small adult
configuration
2: Precocious Puberty
a. onset before 8 in girls, 9 in boys
b. gonadotropin-dependent: central/true precocious puberty; idiopathic or from
secondary to CNS abnormalities
i. 90% idiopathic in girls; almost always secondary in boys
ii. increased gonadotropin secretion, especially at night LH:FSH ratio > 1,
gonadal activation with secondary sexual characteristics
iii. bone age acceleration; final height impairment
c. gonadotropin-independent: pseudo precocious puberty, can be due to adrenal
disorders, gonadal disorders, exogenous sex steroids, McCune Albright
i. suppressed LH and FSH levels due to high circulating levels of sex steroids
ii. growth/bone age acceleration but final overall height impairment
d. McCune Albright Syndrome: fibrous dysplasia of skull and long bone, Caf-Au
Lait patches with serrated borders
i. autonomous endocrine overactivity precocious puberty, thyrotoxi-cosis,
hypercortisolism, pituitary adenomas, hyperparathyroidism
ii. gene mutation for the alpha subunit of G-protein that stimulates cAMP
e. testotoxicosis: familial autosomal dominant, extreme degree of virilization
compared to testicular development, prepubertal levels of FSH and LH
i. caused by a mutation in the LH receptor that leaves it permanently on
ii. does not respond to GnRH analog treatment
f. other aspects of puberty can individually occur without other disease symptoms
(premature thelarche, pubarche, menarche) less cause for concern
g. treatment: arrest maturation until normal age, attenuate/diminish precocious
characteristics, maximize adult height, address emotional/social concerns
i. GnRH analogs are ideal for treatment bind anterior pituitary receptors,
causing down-regulation and desensitization
ii. delays epiphyseal fusion, protects full adult height
3: Delayed Puberty
a. onset after 13 years for girls, 14 years for boys
b. reason for concern could be a result of an underlying cause, and puberty
might never occur huge psychosocial ramifications
c. caused by absence of clear pulsatile secretions of gonadotropin low levels
of FSH and LH
i. bone age is delayed; final height wont be impaired unless severe
3: Growth Disorders
a. GH deficiency: familial inherited GH deficiency, pituitary deficiency
b. primary GH insensitivity: GH receptor deficiency, abnormalities in GH signal
transduction, defect in synthesis of IGF-1
c. secondary GH insensitivity: antibodies to GH, antibodies to GH receptors,
malnutrition, liver disease
d. GH deficiency is diagnosed after 2 stimulation tests <10ng/mL
i. GH levels are difficult to measure in order to diagnose a deficiency
(1) multiple GH molecules, multiple standards, pulsatile secretion
(2) sparse data on normal GH levels; the cutoff is arbitrary
e. patients can be treated by GH or by IGF-1
4: Panhypopituitarism
a. a primary or secondary reduction in the release of all pituitary hormones
i. primary causes: surgery, radiation, tumors, apoplexy (hemorrhage),
infection, infiltration by sarcoid, hemochromatosis, ischemia, carotid
aneurysm, cavernous sinus thrombosis, trauma
ii. secondary causes: a result of disruption to the hypothalamus or the pituitary
stalk, including: tumors, surgery, infection, infiltration and trauma
b. presentation: sequence of hormonal loss is GH FSH/LH TSH ACTH
c. diagnosis: low levels of specific pituitary hormones, low target gland hormones
i. MRI may visualize a tumor
d. treatment: target hormones are usually replaced rather than the pituitary
hormones themselves the most important is cortisol to ward off infection
i. i.e., TSH replaced with thyroxine, or ACTH replaced with hydrocortisone
3: Pituitary/Hypothalamic Pharmacology
a. leuprolide: a GnRH analog with a longer half-life
i. GnRH is normally secreted in pulsatile fashion by the hypothalamus;
stimulates release of FSH and LH from the anterior pituitary
ii. if administered continuously, results in suppressed LH/FSH: used to
suppress prostate cancer growth and endometriosis
iii. if administered in pulsatile fashion, can treat with amenorrhea
iv. side effects: bone pain, feet/ankle swelling, reduced libido
b. somatotropin: GH analog that increases muscle mass
i. used to treat dwarfism, and wasting associated with AIDS or malignancy
ii. side effects: hand/foot edema, thickening of bones/jaw, carpal tunnel,
increased organ growth, decreased insulin sensitivity, hyperglycemia
c. octreotide: a somatostatin analog with a longer half-life
i. somatostatin is released from the hypothalamus; inhibits release of GH,
glucagon, insulin, gastrin, vasoactive intestinal peptide (VIP)
ii. used to treat variceal bleeding, VIPomas, carcinoid syndrome
iii. side effects: gallbladder problems, pancreatitis, hypo/hyperthyroidism
d. dopamine receptor agonists: include bromocriptine and cabergoline, replace
the role of dopamine in inhibiting PRL secretion
i. used to treat prolactinomas and parkinsons
ii. side effects: dizziness, lightheadedness, confusion
e. desmopressin: analog of vasopressin (ADH) with minimal V1 activity (smooth
muscle), increased effect on V2 receptors (the ones involved in reabsorption)
i. used to treat central DI and von Willebrands (stimulates release of vWF)
ii. side effects: transient headache, flushing
f. oxytocin: posterior pituitary hormone that stimulates milk secretion and induces
uterine contractions during labor
i. induces labor; decreases postpartum bleeding by inducing contractions
ii. side effects: chest pain, confusion, vaginal bleeding, palpitations, seizures
1: Thyroid Anatomy/Physiology
a. thyroid glands: regulate growth and metabolic rate through thyroxine (T4,
majority) and triiodothyronine (T3); also makes calcitonin
i. deficiency or excess of TH appears through alterations in energy, weight,
temperature tolerance, GI function, hair/skin quality
ii. calcitonin lowers serum calcium levels by sequestering it in bone but it is
NOT play a major role in calcium metabolism
(1) part of feedback system with PTH; inhibits osteoclast activity
b. anatomy: bi-lobed organ situated in the trachea, it is one of the largest
endocrine organs, and receives a large amount of cardiac output
i. formed in weeks 3-4 from an epithelial outpouching called the thyroid
diverticulum; begins secreting hormone at 18th week
c. histology: made of spherical, closed follicles that are lined with cuboidal cells
i. T3 and T4 are made in the follicular cells and stored in follicles; calcitonin is
made by the parafollicular cells
(1) cell height changes according to the amount of secretion; rich supply of
THYROID DISEASES
Histology [08.06: Dr. C. Brodsky]
Thyroid Physiology [14.06: Dr. J. Arbelle]
Thyroid Pathology [15.06: Dr. G. Amitai]
Thyroid Dysfunction: Thyrotoxicosis & Hypothyroidism [15.06: Dr. J. Arbelle]
Endemic Goiter and Thyroid Nodular Disease [17.06: Dr. J. Arbelle]
1: Hyperthyroidism/Thyrotoxicosis
a. excess in TH, 60% is caused by graves disease; 40% due to misc. causes
including thyroiditis, toxic adenomas, TSH-secreting pituitary tumors, struma
ovarii, and hCG-secreting tumors
i. graves disease: thyroid-stimulating immunoglobulin (TSI) binds TSH
receptors on the thyroid gland increased T3/T4, diffuse non-tender
goiter with bruit, infiltrative ophthalmopathy, pretibial myxedema
(1) associated with other autoimmune disorders
(2) females affected 7 times more than males
ii. plummers disease: hyperfunctioning areas that make excess T3/T4
patchy uptake on thyroid scan
(1) not linked to TSH abnormality or ophthalmopathy
(2) more common in elderly; less severe than graves
iii. subacute thyroiditis: inflammation of thyroid glands spilling of thyroid
hormones transient thyrotoxicosis self-resolution
(1) firm, painful, tender thyroid gland w/fever, increased ESR, radiating pain
(2) usually preceded by upper RI, or occurs postpartum
(3) normal ESR, low radioiodine uptake
iv. neonates: T4, thyroid-stimulating Ig, drugs and iodine all cross placenta;
child can be born with thyrotoxicosis
b. goiter is an enlargement of the thyroid gland, and can be diffuse, single
nodular, or multinodular
i. 80% are colloid nodular goiter, 8% are inflammatory, 7% are neoplastic, 5%
are thyrotoxic
c. presentation: tumor, weight loss, irritability, restlessness, insomnia, heat
intolerance, increased bowel movements/diarrhea, palpitations
i. notable ophthalmologic signs: wide stare, lid lag
ii. warm & moist skin, increased risk of atrial fibrillation, systolic hypertension
d. diagnosis: increased T3/T4; decreased TSH, except in TSH-secreting tumors
i. anti-TSH receptor antibodies for Graves disease
ii. radioactive iodine uptake (RAIU) scan: localized uptake = toxic adenoma,
multinodular thyroid; generalized uptake = graves disease; no uptake =
thyroiditis, struma ovarii
e. treatment: beta-blockers (propanolol) to control adrenergic symptoms; PTU
and methimazole to inhibit TH synthesis and conversion of T4 to T3; radioactive
iodine or surgery to ablate thyroid function
i. radioiodine is contraindicated during pregnancy or nursing
2: Hypothyroidism
a. TH deficiency, 95% result from primary thyroid gland failure; secondary causes
include pituitary failure (secondary) or hypothalamic failure (tertiary)
i. hashimotos thyroiditis: autoimmune destruction characterized by antimicrosomal antibodies w/ lymphocytic infiltration (begins as thyrotoxicosis)
(1) goiterous; other autoimmune destructive thyroiditis is atrophic
i.
3: Thyroid Neoplasms
a. thyroid cancer is the most common endocrine malignancy in the United States
b. risk factors include radiation exposure, men > women, age (malignancy in the
young), family history of MEN 2A/2B
c. presentation: typically presents as a solitary nodule w/ dyspnea,
coughing/choking spells, dysphagia, hoarseness
d. diagnosis: TSH levels; RAIU showing cold nodule with no uptake indicates
biopsy fine needle aspiration to differentiate four types of cancer
i. hot nodules are usually benign adenomas
ii. 15% of biopsies are suspicious or malignant
iii. must rule out multinodular goiter: large follicles with different sizes, lots of
colloid, incomplete capsules around nodes, and pseudopapilla
e. treatment: ablation or medical therapy for benign nodules; surgery for all
cancers except anaplastic carcinoma
TYPE
PREVALENCE
CHARACTERISTICS
TREATMENT
Papillary
Carcinoma
70-80%
lobectomy or total
thyroidectomy,
radioiodine
Follicular
Carcinoma
10-20%
total thyroidectomy
+ postoperative
iodine ablation
total thyroidectomy
chemotherapy and
radiation
Medullary
Carcinoma
5%
Anaplastic
Carcinoma
5%
4: Iodine Deficiency
a. effects vary according to the age of onset
i. fetus: abortions, stillbirths, congenital abnormalities, endemic cretinism
ii. neonate: goiter, hypothyroidism, endemic mental retardation
iii. child/adolescent: impaired mental function, retarded physical development
iv. adult: goiter, impaired mental function, hypo/hyper thyroidism
b. geographically occurs in mountainous areas and river valleys
i. some endemic forms are exacerbated by indigenous foods that contain
thiocyanates, which impairs TH production
c. 1.5 billion people are exposed to iodine deficiency, but they are subclinical
d. 50-200 mcg/day is the basic dietary requirement; higher for pregnant mothers,
infants, and breastfeeding women)
i. intake can be measured by urine sample
e. goiter in iodine deficiency is caused by an increase in TSH
with iodine deficiency, the body tries to maintain the level of circulating T3
but the anterior pituitary still releases TSH because it is regulated by
intracellular conversion of T4 into T3, and T4 levels are low
5: Thyroid Pharmacology
a. levothyroxine: a T4 analog used to treat hypothyroidism
i. binds nuclear receptors and leads to increased protein synthesis, increased
metabolic rate, increased beta-receptors/sensitivity to catecholamines
(1) T3 analogs are not used because they can cause heart failure but is
used to treat myxedema coma
ii. side effects: signs and symptoms of thyrotoxicosis
b. thionamides: methimazole and propylthiouracil inhibit oxidation and
organification of iodine in TH synthesis
i. used to treat thyrotoxicosis; PTU is preferred for nursing mothers
ii. PTU also inhibits peripheral conversion of T4 to T3
iii. side effects: rash, urticaria, fever, nausea, agranulocytosis,
thrombocytopenia, acute hepatic necrosis, vasculitis
iv. both drugs are contraindicated during pregnancy (they cross the placenta)
c. radioiodine: selectively concentrated in the thyroid gland; emits beta and
gamma radiation
i. large doses are used for thyroid storm and before thyroidectomy
ii. used for hyperthyroidism and adjunctive treatment in some thyroid cancers
iii. side effects: metallic taste, excessive salivation, diarrhea, rash
1: Parathyroid Anatomy/Physiology
a. the main function of the parathyroid is calcium homeostasis and bone health
i. total body calcium: 99% in bone reservoirs, 0.9% in ICF, and 0.1% in ECF
(1) ECF component is serum calcium 50% is bound to plasma proteins,
10% is complexed with anions (phosphate, citrate), 40% is free (ionized
and biologically active)
ii. parathyroid hormone is the main player; acts on kidneys and bone to
increase serum calcium while decreasing serum phosphate
iii. PTH does not work alone; Vitamin D is also involved in calcium regulation
(1) vitamin D increases intestinal absorption of calcium and phosphate;
works with PTH to promote bone resorption, resulting in elevated levels
of calcium and phosphate
b. anatomy: four small pea-sized structures attached to the posterior thyroid gland
i. located outside the thyroids fibrous capsule
ii. separated into two superior and two inferior parathyroids; both sets supplied
by the inferior thyroid arteries and drain into thyroid vein plexus
iii. derived from pharyngeal pouch endoderm
c. histology: parathyroids contain chief cell and oxyphil cell populations
encapsulated by connective tissues
i. chief: predominant cells w/ secretory granules that contain PTH; arranged
into curvilinear cords separated by capillaries
ii. oxyphil: large cells w/ abundant acidophilic mitochondria; unknown function
2: Parathyroid Hormone
a. PTH: polypeptide hormone synthesized and secreted by parathyroid chief cells
i. starts as a larger, inactive preprohormone; secreted form is 84 AAs
ii. rapidly degraded by the kidneys after secretion, but smaller peptide
fragments of the hormone are still active after several hours
iii. amino-terminal end is responsible for biological action
b. overall, it increases serum calcium and decreases serum phosphate
c. release is stimulated by low serum calcium, and inhibited by high levels
i. CaSR is a G-protein coupled calcium sensing receptor (7 transmembrane
domains) that binds Ca2+ in the ECF intracellular signals decrease PTH
ii. mild decreases in magnesium also stimulates secretion but severe
hypomagnesemia inhibits secretion
iii. also inhibited by high levels of 1,25 (OH)2 D
d. mechanism: alters bone turnover, renal tubule reabsorption and vit. D activation
i. increased bone resorption: stimulates both osteoclasts and osteoblasts, but
unequally favoring bone resorption increased calcium and phosphate
3: Vitamin D
a. main forms of vitamin D are ergocalciferol (D2) and cholecalciferol (D3)
i. D2 is made by plants and fungi not made in the human body, less potent
ii. D3 is made in animals, and also produced in the skin
(1) UV light reacts with 7-dehydrocholesterol vitamin D3
b. D3 is initially inactive activation occurs in the liver and kidney
i. in the liver: undergoes hydroxylation to form 25-hydroxycholecalciferol
rate limiting step, determines the amount of active vitamin D
(1) inactive form is stored in the liver
(2) negative feedback from product inhibits this first hydroxylation
ii. in the kidney: 1alpha-hydroxylase hydroxylates 25-hydroxycholecalciferol a
second time 1,25-dihydroxycholecalciferol [1,25 (OH)2 vitamin D]
(1) this is the active form calcitrol
(a) calcitrol formation is increased by low calcium and phosphate levels
(2) 1alpha-hydroxylase is upregulated by PTH
c. mechanism: calcitrol raises extracellular levels of calcium and phosphate and
promotes mineralization of bone
i. increases intestinal calcium and phosphate absorption: upregulates gene
transcription of a calcium-binding protein (calbindin D-28K) in the intestinal
brush border better absorption of dietary calcium
ii. increases bone resorption of calcium and phosphate: promotes resorption
of calcium and phosphate by PTH ineffective without calcitrol
iii. increases renal reabsroption of calcium and phosphate (minor): promotes
increased reabsorption of both ions by renal tubules, but not a major effect
d. vitamin D receptor: cytoplasmic protein that binds D3; complex binds with
RXR moves to nucleus to affect transcription
e. vitamin D deficiency can be due to disturbances in sun exposure or dietary
intake; 25 OH D deficiency can be caused by phenobarbitol, biliary cirrhosis,
diphenylhydantoin
i. deficiency is < 10ng/mL; insufficiency is 10-20, sufficiency is 30-100
ii. deficiency causes rickets/osteomalacia; insufficiency causes osteoporosis
f. vitamin D resistance type I: inability to convert 25 OH D 1,25 OH2 D
g. vitamin D resistance type II: malfunctioning 1,25 OH2 D receptor; occurs in
postmenopausal women with loss of estrogen
CALCIUM DISORDERS
Hypo/Hyper Calcemia [16.06: Prof. S. Shanny]
1: Primary Hyperparathyroidism
a. inappropriate excess secretion of PTH hypercalcemia
i. benign parathyroid adenoma is responsible in 80% of cases
ii. parathyroid gland hyperplasia accounts for remaining 20%
b. presentation: usually asymptomatic, discovered based on elevated calcium
levels; symptomatic patients present with renal, GI or neurologic symptoms
i. renal: polyuria, hypercalcinuria, renal stones can lead to renal failure
ii. skeletal: bone pain and aches; increased bone resorption and osteopenia
iii. GI: nausea, vomiting, weight loss, constipation, anorexia, peptic ulcer
disease, acute pancreatitis
iv. neurologic: mental status changes, depression, fatigue
v. hypercalcemic crisis: polyuria, dehydration, mental status changes
c. diagnosis: increased serum calcium, decreased serum phosphate, increased
PTH, short QT interval on EKG; chloride is often elevated
3: Primary Hypoparathyroidism
a. caused by accidental surgical removal, pseudohypoparthyroidism from endorgan PTH resistance, di georges syndrome (decreasing order of frequency)
i. di georges: failure of third and fourth pharyngeal pouch development
b. presentation: neuromuscular excitability due to hypocalcemia
i. muscle fatigue, weakness, numbness, tingling in extremities, psychosis
ii. chvosteks sign: tapping of the facial nerve in front of the ear upper lip
and facial muscles contract
iii. trousseaus sign: inflation of a blood pressure cuff higher than systolic
pressure carpal spasms
iv. basal ganglia calcifications can cause parkinsonsian symptoms; ocular lens
can be calcified cataracts
c. diagnosis: decreased PTH, decreased calcium, increased phosphate, increased
QT interval on EKG, imaging can reveal basal ganglia calcifications
i. serum albumin, vitamin D, Mg, alkaline phosphatase and urine calcium
levels should be checked as well
d. treatment: calcium supplements, vitamin D supplements, and IV calcium
gluconate for acute symptoms
serum
phosphate
PTH
primary hyperparathyroidism
primary hypoparathyroidism
pseudo-hypoparathyroidism
or normal
5: Thyroid Pharmacology
a. bisphosphonates: stabilizes bony matrix, coats hydroxyapatite to prevent
osteoclasts from breaking down bone
i. used in postmenopausal osteoporosis and in Pagets disease
ii. side effects: heartburn, upset stomach, joint/back pain, headache
b. calcitonin: lowers serum calcium, has analgesic properties for bone pain
i. used in hypercalcemic states, administered by nasal spray
ii. side effects: runny nose, nasal discomfort, flushing
c. calcitriol: activated form of vitamin D, increases calcium absorption in kidneys
i.
used in hypocalcemia
ADRENAL GLAND
ADRENAL GLAND
Histology [08.06: Dr. C. Brodsky]
Adrenal Physiology [13.06: Prof. E. Lieberman]
1: Adrenal Overview
a. the adrenal glands main function is to coordinate the bodys response to stress
b. sit above the kidneys, retroperitoneal, asymmetric, with a rich blood supply
i. right is shaped like a pyramid; left is shaped like a crescent
c. adrenal medulla: inner portion, an extension of the sympathetic nervous
system; secretes catecholamines epinephrine and norepinephrine
i. derived from neural crest cells, which differentiate into chromaffin cells
ii. when fixed in chrome salts, norepinephrine stains darker than epinephrine
d. adrenal cortex: outer portion, synthesizes steroid hormones (corticosteroids)
i. secretes cortisol for stress response, aldosterone for water/electrolyte
balance, testosterone for masculinizing effects
ii. made of three distinct layers (Salt Sugar Sex)
(1) zona glomerulosa: outermost layer, relatively thin, comprised of cells
that contain aldosterone synthase only layer that makes aldosterone
(a) controlled by potassium and angiotensin II levels; loss of function
leads to hyponatremia, hypovolemia and hyperkalemia
(2) zona fasciculate: largest layer, fascicles of cells that synthesize and
secrete glucocorticoids and small amounts of androgens/estrogens
(a) controlled by ACTH; loss of function leads to circulatory failure,
decreased ability to mobilize sugars
(3) zona reticularis: deepest layer, made of cells that synthesize adrenal
androgens and small amounts of glucocorticoids and estrogens
(a) controlled by ACTH; loss of function leads to little physiologic effect
e. steroid hormone synthesis: constitutive, made on demand using cholesterol
i. free cholesterol inside adrenal cortical cells is transported to mitochondria;
followed by a series of reactions that act on the various carbons
(1) 20% of cholesterol is made de novo; remainder is from circulating LDL
ii. cholesterol desmolase converts cholesterol to pregnenolone rate
limiting step, conserved across all of adrenal cortex
(1) ACTH and angiotensin II stimulate this conversion
(2) inhibited by ketoconazole
iii. pregnenolone is converted to 17alpha-hydroxyprogesterone by 17alphahydroxylase 21alpha-hydroxylase 11-!-hydroxylase cortisol
iv. pregnenolone is converted to progesterone by 3-!-hydroxysteroid
dehydrogenase 21alpha-hydroxylase 11-!-hydroxylase
aldosterone synthase aldosterone
(1) 21-hydroxylase deficiency is the most common form of congenital
adrenal hyperplasia; leads to decreased levels of glucocorticoids and
mineralocorticoids rise in androgens
v. 17-"-hydroxylase converts pregnenolone and progesterone into
androstenedione and DHEA precursors of adrenal androgens (C19)
vi. end products are aldosterone, cortisol, and androgens
2: Glucocorticoids
a. the hypothalamus, anterior pituitary, and adrenal cortex interact to coordinate
glucocorticoid synthesis initiated by secretion of CRH
i. CRH secretion is triggered by hypoglycemia, trauma, illness, fever,
psychological stress, and physical exertion
ii. CRH stimulates corticotrophs of the anterior pituitary to release ACTH
iii. ACTH upregulates desmolase, the rate-limiting step in cortisol synthesis
(1) also promotes adrenal gland hypertrophy
iv. system is inhibited by feedback regulation; high levels of cortisol inhibit
CRH and ACTH secretion
b. glucocorticoids get their name for their effects on blood glucose levels, but also
act on immune function, bone turnover, CV function, lung maturation
c. cortisol: predominant glucocorticoid, increases lipolysis in adipose tissue,
stimulates gluconeogenesis, upregulates vascular adrenergic (alpha1) receptors
3: Mineralocorticoids (Aldosterone)
a. aldosterone is the chief mineralocorticoid; secretion is initiated/promoted by
small amounts of ACTH, but the rate of secretion is determined by other factors
i. secretion is increased by high serum potassium, RAS, angiotensin II
ii. secretion is decreased by high serum sodium (but w/minimal effect)
b. aldosterone has three major effects: increased sodium reabsorption, increased
BP, and increased potassium excretion
i. increased sodium reabsorption: stimulates synthesis of new sodium
channels in renal collecting tubules reduced sodium excretion in urine
ii. increased arterial pressure: serum sodium concentration does not change
with increased sodium reabsorption since water is absorbed with it
increased extracellular volume increased arterial pressure
iii. increased potassium secretion: induces opening of large potassium
channels in renal collecting ducts increased potassium secretion
c. renin-angiotensin-aldosterone mechanism: aldosterone works in conjuction
with renin and angiotensin to elevate blood pressure
i. liver creates a circulating level of angiotensinogen
ii. drop in blood pressure causes the kidneys to secrete renin cleaves
angiotensinogen into angiotensin 1
iii. ACE converts angiotensin 1 angiotensin II
iv. angiotensin II acts on the brain to promote thirst, blood vessels to
vasoconstrict, and adrenals to secrete aldosterone water retention
4: Adrenal Androgens
a. set of relatively weak androgens that make up a small percent of sex steroids
i. androstenedione, DHEA, dehydroepiandrosterone sulfate (DHEA-S)
b. minor role in homeostasis, but important during certain developmental stages
i. fetal development: placenta is incapable of synthesizing sex steroids de
novo, so it produces androgens and estrogens from adrenal precursors
ii. adrenarche: stage of adrenal maturation marked by increased androgen
synthesis pubic and axillary hair growth
(1) weak adrenal androgens are peripherally converted to more potent ones
that produce secondary sexual differentiation in both sexes
iii. menopause: ovarian estrogen production has ceased, but postmenopausal
women have some estrogen function from conversion of androstenedione
(adrenals, ovaries) to estrone by aromatase
ADRENAL DISORDERS
Adrenal Pathophysiology [10.06: Prof. I. Liberman]
Adrenal Pathology [15.06: Dr. G. Amitai]
cortisol
ACTH
1: Cushings Syndrome
a. excess of cortisol, most commonly caused by iatrogenic overdose; can also be
caused by pituitary adenomas, adrenal tumors, and ectopic ACTH production
i. pituitary adenomas can cause the syndrome due to excess ACTH synthesis
ii. small cell carcinoma of the lung and bronchial carcinoid tumors are
associated with ectopic ACTH production
b. presentation: features consistent w/ excess cortisol: central obesity, moon
facies, buffalo hump, hypertension, glucose intolerance, purple striae, muscle
wasting/weakness, osteoporosis, depression, decreased immunity
i. decreased peripheral glucose utilization, increased hepatic gluconeogenesis
c. diagnosis: initial screen is the low-dose dexamethasone suppression test;
0.5mg of dexamethasone every six hours for 48 hours
i. normal response is complete suppression of ACTH; if cortisol is detectable,
the patient has Cushings syndrome
ii. followed by a 24-hour urinary free cortisol excretion to confirm diagnosis
iii. high-dose suppression test can then be used to differentiate between
Pituitary Cushings and Adrenal/Ectopic Cushings
(1) cortisol is suppressed in the former, and not suppressed in the latter
(2) CRH test can also be used; 0.1 g/kg of human CRH is given, and blood
is assayed for ACTH and cortisol at times -15, 0, 15, 30, 60, 90, 120.
(a) exaggerated response indicates pituitary dependant Cushings
Disease; flat response indicates ectopic ACTH production
serum
calcium
serum
phosphate
high-dose
dexamethasone test
cortisol suppressed
5: Pheochromocytoma
a. neuroendocrine tumor of chromaffin cells over-secretion of epinephrine and
norepinephrine; mostly located in adrenal medulla
i. 10% are familial, 10% are bilateral, 10% are malignant, 10% occur in
children, and 10% are extra-adrenal
b. associated with multiple endocrine neoplasia type IIA and IIB; inhereited as
autosomal dominant disorders
i. MEN type 1 (Wermers syndrome) = three Ps
(1) parathyroid hyperplasia, pancreatic islet cell tumors, pituitary tumors
ii. MEN type 2A (Sipples syndrome) = MPH
(1) medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism
iii. MEN type 2B = MMP
(1) medullary thyroid carcinoma, mucosal neuromas, pheochromocytoma
c. presentation: hypertension, palpitation, anxiety and weight loss
d. diagnosis: 24hr urinary metanephrine & vanillylmandelic acid (breakdown
products of catecholamines)
i. clonidine suppression test NE will remain elevated in patients with
pheochromocytoma (normally will be suppressed)
e. treatment: surgical removal, preceded by adrenergic blockers (propanolol)
i. medical therapy uses both alpha and beta blockers
1: Obesity/Adipose Tissue
a. adipose tissue secretes several hormones and cytokines; obesity leads to
overproduction of these products end resistance
i. secretes angiotensinogen, which is made into a vasoconstrictor
ii. plasminogen activator inhibitor-1 (PAI-1) favors formation of microthrombi
iii. IL-6 is a pro-inflammatory, implicated in insulin resistance and beta-cell
apoptosis in diabetes
b. leptin: secreted by adipocytes, acts on the hypothalamus to decrease appetite
and increase metabolism; levels are proportional to total body fat
i. works via the JAK/STAT pathway and MAP kinase
ii. resistance leads to hypertension from excess stimulation of the kidneys
c. adiponectin: secreted by adipocytes, associated w/ weight loss
d. visceral fat is more correlated with negative health outcomes
2: Drugs
a. orlistat: inhibits intestinal lipases decreased intestinal absorption
3: Glucagon
PANCREAS, INSULIN, GLUCAGON
Histology [08.06: Dr. C. Brodsky]
Diabetes type 1+2 Definition and Pathophysiology [20.06: Dr. I. Harman]
1: Pancreas Anatomy/Histology
a. the pancreas is a multi-functional organ of the endocrine and digestive system
i. vital role in carbohydrate, lipid, and protein metabolism
b. located behind the stomach, between duodenum and spleen; divided into four
segments (head, neck, body and tail)
i. the head is next to the duodenum, and the tail is next to the spleen
ii. organ lies transversely across the retroperitoneum
c. the pancreas is actually a fusion of two embryonic parts; exocrine function
begins shortly after birth, but endocrine signaling starts at weeks 10-15
d. islets of langerhans: clusters of hormone producing cells, interspersed within
pancreatic exocrine tissue; ~ one million through pancreas, mostly in the tail
i. alpha cells: 20% of islet cells, secretes glucagon
ii. beta cells: 70%, secretes insulin
iii. delta cells: <5%, secretes somatostatin
iv. f-type: rare, secretes pancreatic polypeptide
e. autonomic nerve fibers innervate the blood vessels and endocrine cells in islets
i. only 10% of islet cells are close to nerve fibers; the remaining receive
signals through gap junctions
2: Insulin
a. protein made of two polypeptide chains (A and B) joined by disulfide bonds
i. made from a preprohormone; proteolytic cleavage occurs in the rough ER
and the golgi complex to an active form of 51 amino acids
(1) inactive remainder is C-peptide (31 amino acids)
(2) equimolar amounts of C-peptide and insulin are released
b. secreted by pancreas into hepatic portal system; only 50% leaves the liver
c. glucose is the most powerful stimulus for insulin release
i. diffuses into beta cells via GLUT-2; intracellular glucose equilibrates with
serum glucose concentration
(1) increased glucose levels glycolytic pathway increased ATP:ADP
ratio ATP-sensitive potassium channels close depolarization
opening of calcium channels calcium facilitates insulin release
ii. also affected by cAMP; serum glucose stimulates cAMP formation within
the beta cell mobilized calcium increased insulin secretion
iii. secretion is a biphasic response; sharp peak at time of ingestion, then a
slow, lower peak over the course of three hours
(1) diabetics lose the first peak hyperglycemic/hyperlipidemic peaks
d. insulin receptor: member of GF family, consists of two extracellular alpha
subunits and two transmembrane beta subunits linked by disulfide bonds
i. insulin binds the alpha subunits autophosphorylation beta activation
ii. beta subunits have tyrosine kinase activity activation recruits other
proteins (adapter molecules, kinases, phosphatases) 2 pathways
(1) mitogenic pathway: responsible for growth-promoting effects of
insuline due to activation of the MAP kinase cascade
(2) metabolic pathway: responsible for alterations in nutrient metabolism
(a) activation of phosphatidylinositol-3-kinase (PI3-K) leads to GLUT-4
transporter insertion in cellular membranes increased anabolism
iii. receptor spill-over occurs with IGF-1
iv. down-regulation: continued exposure to insulin leads to internalization of
insulin-bound receptors desensitization of target tissues
(1) insulin receptors are up-regulated in response to low insulin levels
e. action on carbohydrate & lipid metabolism mostly occur in liver, muscle and fat
i. liver: promotes storing energy, and reduces catabolism
(1) upregulation of glucokinase and glycogen synthase increased
glycogen formation
(2) inhibits glycogen phosphorylase reduced glycogenolysis
(3) inhibits phosphofructokinase reduced gluconeogenesis
(4) promotes trigylceride synthesis; inhibits fatty acid/AA catabolism
ii. muscle: increased uptake, decreased degradation
(1) insertion of GLUT-4 on cell membranes increased glucose uptake
4: Somatostatin
a. small polypeptide secreted by pancreatic delta cells in response to high levels
of blood glucose, amino acids, fatty acids and gastric hormones
b. paracrine effect: decreases secretion of insulin and glucagon
c. decreases gastric duodenal and gallbladder motility
d. decreases function of intestinal mucosa (decreases absorption and secretion)
PANCREATIC DISORDERS
Diabetes type 1+2 Definition and Pathophysiology [20.06: Dr. I. Harman]
Oral Hypoglycemics Drugs [21.06: Dr. M. Maislos]
Complications Diabetes and DKA [21.06: Dr. I. Harman]
Hypoglycemia [22.06: Dr. M. Maislos]
1: Diabetes Mellitus
a. hyperglycemia is the key feature in DM, either due to reduced insulin secretion
(Type 1) or tissues resistance to insulin (Type 2)
b. major concern is the associated comorbiditiess: neuropathy, microvascular
disease, macrovascular disease
i. in diabetic patients, 80% are obese, 60% have hypertension, 50% have lipid
abnormalities, 60% have neuropathy
ii. leading cause of renal failure, blindness, lower limb amputations
c. type I: autoimmune destruction of beta cells in pancreas, unknown cause
i. associated with other autoimmune disorders
ii. not completely genetic; only 50% concordance in identical twins
(1) principal susceptibility locus for type 1 resides in the region that
encodes the class II MHC molecules on chromosome 6p21 (HLA-D)
iii. after initial beta-cell failure, there is a temporary restoration of beta cell
function progressive deterioration
iv. histology: reduction in number and size of islets w/ leukocytic infiltration
d. type II: has traits of both impaired insulin secretion and insulin resistance
impaired glucose tolerance
i. begins as resistance, but overproduction of insulin leads to beta-cell failure
ii. high genetic correlation
iii. incretins are released in the gut in response to food; they increase insulin
production and reduce glucagon secretion, and are involved in type II
(1) GLP-1 from L cells located primarily in the distal gut (ileum and colon),
and GIP from K cells in the proximal gut
(2) incretin effect describes the higher release of insulin from oral glucose
than from IV glucose; type II diabetics have diminished incretin effect
(3) overall, incretins work to reduce hepatic glucose mobilization
iv. histology: subtle reduction in islet cell mass, amyloid replacement
e. gestational diabetes is a transient form that occurs in 2-5% of pregnancies;
20-50% of these women will develop Type II later on
f. presentation: polyuria, polydipsia glucose-induced osmotic diuresis
2: Diabetic Ketoacidosis
a. a complication of DM-1, an absence of insulin results in hypergylcemia,
metabolic acidosis and nitrogen imbalance
i. decreased insulin increased lipolysis increased glycerol and free fatty
acids beta-oxidation of free fatty acids increased ketones
ii. hyperglycemia hyperosmolality osmotic diuresis dehydration
iii. acidosis is a combination of increased hepatic ketone production,
incomplete glucose utilization (lactic acid) and decreased bicarbonate
iv. negative nitrogen balance due to increased use of amino acids for
gluconeogenesis, increased proteolysis and decreased muscle synthesis
b. presentation: tachycardia, kussmauls respirations, fruity breath, dehydration,
orthostatic hypotension, altered consciousness, decreased BP, no fever
c. diagnosis: nitroprusside determination, measuring acetoacetate levels; glucose
and ketones in urine, pH < 7.3, pCO2 < 40
d. treatment: replace fluids, administer IV insulin, identify/treat underlying cause
i. keep an eye on potassium levels; carbonate given in extreme acidosis
3: Hyperinsulinemia/Syndrome X
a. an alternate outcome to insulin resistance, defined by macrovascular issues;
considered a precursor to DM type II
b. results in hypertrigylceremia with increased VLDL and decreased HDL
i. hypertension due to increased sodium absorption, enhanced adrenergic
tone due to increased RAS, vascular hypertrophy from GF effect of insulin
ii. hyperuricemia due to decreased uric acid clearance
c. diagnosis requires high waist circumference and two CV factors
i. high triglycerides, low HDL, high BP, or FPG>100mg/dL
4: Insulinoma
a. an uncommon cause of hypoglycemia in non-diabetics, result from tumors of
beta cells in the pancreas
i. often associated with MEN 1 syndrome; other causes must be ruled out
b. presentation: patients with insulinomas present with whipples triad fasting
hypoglycemia, symptoms of hypoglycemia, relief of symptoms after IV glucose
i. hypoglycemic symptoms mimic excess epinephrine: sweating, tremor,
tachycardia, CNS dysfunction (dizziness, headache, altered mental state)
c. diagnosis: increased insulin and C-peptide
i. both insulin and c-peptide need to be elevated; if c-peptide is low, it is
factitious hypoglycemia
d. treatment: surgical resection; for acute treatment, sugar containing food if
patient cant eat, D50W is given
5: Diabetes Pharmacology
a. insulin: can be given SC, usually given as two-thirds of daily dose in the
morning, and a third at night; given by IV for diabetic ketoacidosis
i. used by all DM-1 diabetics, and some DM-2
ii. drawbacks: slow onset, must be given 20 min before meals, inconvenient,
lasts 12 hours, doesnt not mimic physiologic conditions
iii. physicians are concerned about hypoglycemic events and weight gain
iv. side effects: hypoglycemia
b. insulin variants: attempt to address some of the normal insulins drawbacks
the ideal version would be administered once a day, without any peaks
i. insulin detemir: binds albumin better, acts for 20 hours at lower levels
ii. insulin glargine: provides a peak-less profile lasting 24 hours
c. sulfonylureas: inhibits potassium channels on beta cells, preventing hyperpolarization more depolarization increased calcium influx more insulin
i. used to control glucose in DM-2 if uncontrolled by diet and exercise
ii. cheap but higher risk of side effects; requires 30% of beta-cell function to
be effective, and better for thin patients
iii. first generation is tolbutamide; second generations are glipizide & glyburide
iv. side effects: hypoglycemia, weight gain, hypersensitivity
d. metformin: decreases hepatic glucose production and increases peripheral
insulin sensitivity; extremely good and safe, but unknown mechanism
i. biguanide family; does not cause hypoglycemia or weight gain
ii. first-line treatment for obese diabetic patients; some synergism w/
sulfonylureas in patients without renal failure (cleared by kidneys)
iii. side effects: lactic acidosis, GI distress
e. acarbose: inhibits alpha-glycosidase decreased carbohydrate absorption
from the GI tract decreased insulin demand
i. potentially useful in DM-2, but not well tolerated
ii. side effects: flatulence, diarrhea, abdominal discomfort
f. thiazolidinediones (rosiglitazone, pioglitazone): binds nuclear peroxisome
proliferator-activated receptor (PPAR) to control transcription of insulinresponsive genes insulin sensitization, decreased hepatic gluconeogenesis,
insulin receptor upregulation
i. used in DM-2 in absence of liver disease
ii. side effects: weight gain, edema, liver function abnormalities
g. repaglinide: works like sulfonylureas; stimulates release of insulin
h. incretins: hormones naturally secreted in the gut after eating, increases insulin
i. the two of interest are glucagon-like peptide-1 (GLP-1), and glucosedependent insulinotropic polypeptide (GIP)
ii. GLP-1 is rapidly degraded by DPP-4; DPP-4 inhibitors are in development
iii. GLP analogues: exenetide, liraglutide administered by injection